We, the present inventors, already found that an isocarbostyril derivative represented by the formula ##STR1## namely a compound previously named as 4-{3-[2-(2-methoxyphenoxy)-1-methylethylamino]-2-hydroxypropoxy}-isocarbos tyril and now named as 1-[2'-(o-methoxyphenoxy)-1'-methylethylamino]-3-(4"-isocarboxystyriloxy)-2 -propanol is a new compound which is useful as a medicinal compound for the therapeutic treatment of cardiovascular diseases (see Japanese patent application unexamined first publication "Kokai" No. 116269/84 published July 5, 1984 of Japanese patent application No. 225996/82; European patent application publication No. 0113910 A1 published July 25, 1984; pending U.S. patent application Ser. No. 562,237 filed Dec. 16, 1983, now U.S. Pat. No. 4,526,893). In the specification of these earlier patent applications, we have suggested that the particular compound mentioned above and its analogues contains two asymmetric carbon atoms in the molecule thereof and there would theoretically be a possibility that four different optical isomers should exist for said particular compound. In the past, however, actually we did not succeed in isolating independently such four optical isomers from said compound, so that detailed properties of each of such optical isomers were not yet elucidated.
Hithertobefore, it is known that a conventional optical resolution method comprising reacting any optically active chemical reagent with a compound containing asymmetric arbon atom(s) to be optically resolved is not suitable for separately obtaining or isolating the theoretically existing four optical isomers from such a compound containing two asymmetric carbon atoms in the molecule thereof. For the purpose of isolating the theoretically existing four optical isomers separately or independently from a compound containing two asymmetric carbon atoms in the molecule, therefore, there has usually been adopted in the prior art a method which comprises preparing synthetically, in a first stage, said compound in the form of a mixture of two optical isomers (diastereomers) where the first of the two asymmetric carbon atoms present has, initially, a predetermined particular configuration, (R) or (S), while the second of the two asymmetric carbon atoms may have the configuration (R) or the configuration (S) in the respective molecules of the isomers, namely in the form of the mixture of such two diastereomers which are assumed so from the stand-point of the second one of the two asymmetric carbon atoms. Then the compound as prepared in the first stage as a mixture of two diastereomers is subjected to fractional crystallization or other optical resolution methods to isolate said two diastereomers from each other. In a further step, said compound in the form of a mixture of the further two diastereomers where the first one of the two asymmetric carbon atoms present here has initially a predetermined particular configuration (S) or (R), other than that shown by the first asymmetric carbon atom of the first-prepared two diastereomers. However, the second asymmetric carbon atom may have the configuration (R) or (S) in the respective molecules of the further two diastereomers. Lastly the compound as prepared in the aforesaid further stage as the further mixed two diastereomers is subjected to fractional crystallization or other optical resolution methods to isolate said further two diastereomers from each other so that the four different optically active isomers are isolated from each other are ultimately afforded.
With the compound of the formula ##STR2## theoretically, it may appear to be equally possible that four different optically active isocarbostyrils in the form of the (S-S)-isomer, (S-R)-isomer, (R-S)-isomer and (R-R)-isomer, respectively, represented by a general formula (II): ##STR3## wherein the asterisks * each denote either the (S)-configuration or (R)-configuration and more exactly, each carbon atom having the asterisk * attached thereto as shown exhibits either the (S)-configuration or the (R)-configuration are isolated from each other and thus obtained according to the prior art method as acknowledged just above. For instance, if the compound represented by the formula (III): ##STR4## wherein the asterisk * denotes a predetermined particular one of the (S)-configuration and (R)-configuration, can be prepared in a first stage as the mixed two diastereomers which are assumed so from the stand-point of the second asymmetric carbon atom having no asterisk attached thereto, followed by isolating these mixed two diastereomers into each independently existing diastereomer by any suitable optical resolution method, then, in theory the compound of the formula (III) where the asymmetric carbon atom having the asterisk attached thereto as shown exhibits here the (R)- or (S)-configuration other than that of the compound (III) diastereomers as prepared in the first stage, can subsequently be prepared in a further stage as the further mixed two diastereomers, followed by isolating said further mixed two diastereomers into each independently existing diastereomer by any suitable optical resolution method.
Actually, however, as far as the present inventors have tested in various ways, the compounds of the formula (III) themselves obtained as the mixed two diastereomers cannot be isolated into an independently existing single diastereomer by subjecting them to various conventional optical resolution methods which include, for example, fractional crystallization or different chromatographic methods and the like.
As a result of our further research, we have now found that when the compound of the formula (III) has once been converted into an oxazolidone derivative represented by the formula (I): ##STR5## wherein the first asymmetric carbon atom having the asterisk attached thereto as shown exhibits either the (S)-configuration or the (R)-configuration and wherein the second asymmetric carbon atom having no asterisk attached thereto may exhibit the (R)-configuration or the (S)-configuration, this oxazolidone derivative (I) obtained as the mixed two diastereomers can easily be isolated into its independently existing single diastereomers by a conventional isolation technique, for example, chromatography, including liquid chromatography, column chromatography and other chromatographic procedures. When the oxazolidone derivative of the formula (I) is isolated into its independently existing single diastereomers, followed by hydrolyzing each single diastereomer to give the corresponding actually active 1-[2'-(o-methoxyphenoxy)-1'-methylethylamino]-3-(4"-isocarbostyriloxy)-2-p ropanol generically represented by the general formula (II), there can be afforded the four different optically active isocarbostyril derivatives as specified above and represented by the general formula (II), each in the form of an independently isolated new substance.